Iodine preparation composition

ABSTRACT

An iodine preparation composition suitable for use on wounds comprising an iodide source, an oxidant and a buffer characterized in that the iodide is held separately from the oxidant until the point of use, and that the buffer is capable of maintaining the pH of the composition at between pH 45 and pH 6 so that iodine is generated at a physiologically acceptable dose rate.

This invention relates to an antimicrobial composition which can beapplied to wounds, cuts, abrasions or burns for the prevention ortreatment of infections. More particularly the invention relates to acomposition capable of providing effective antimicrobial activity whileat the same time avoiding wound and skin irritation and retardation ofwound healing.

Topical antimicrobial materials and preparations containing them havelong been recognised as important parts of antisepsis of intact skin andwounds. Iodine has been recognized as an antimicrobial agent witheffectiveness against a wide range of micro-organisms. There are howeverseveral barriers to making an effective antimicrobial composition forapplication to wounds based on iodine. One problem is that iodine tendsto react with organic materials found in the wound other than theintended microbial targets. This means that to be effective, iodineneeds to be included at high levels such as 0.9% by weight, as describedin “Handbook of Wound Dressings” edited by Stephen Thomas, 1994 Journalof Wound Care. At such levels and with continued use iodine may haveundesirable local side effects such as cell toxicity, hypersensitivityreactions, skin staining, and unpleasant odour and systemic adverseeffects such as metabolic acidosis and impairment of renal function. Forthis reason application of iodine is recommended at levels below 1.35 gin one week.

A further problem is that iodine has a relatively short shelf life whenin aqueous solution meaning either that compositions which include waterneed to be freshly prepared before each application or again that iodineis included at high levels. These factors limit product form.

In the past these problems with iodine have sought to be addressed bythe use of iodophors which act as a release mechanism for iodine.Iodophors are readily dissociable, loose complexes of iodine withpolymers or surfactants. Iodophor compositions are not best suited touse on wounds because when applied to a wound, all iodine present in thecomposition is readily available for reaction and therefore the adversereactions associated with high levels of iodine are not necessarilyavoided.

There thus exists a need for a composition which delivers iodine to awound at a rate which is high enough to provide effective antisepsis butwhich is low enough to avoid the problems of adverse reactionsassociated with high levels of iodine.

GB-B-2276546 to Diversey relates to improved iodophors which areprepared at the point of use. The composition comprises an iodidesource, an oxidant and an acid source, the oxidant becoming active onlywhen the composition is dissolved in an aqueous medium. The compositionis said to overcome the stability problems associated with producingteat dip/spray iodine formulations for use in the control of bovinemastitis. The rate of generation of iodine needed for these topicalformulations for use on intact skin far exceeds that tolerable to awound. In these compositions such high levels of iodine are generatedthat a hydrotrope must be included to prevent the iodine fromcrystallising. In addition, iodine has a complex chemistry in aqueoussolutions and exists in a number of equilibria. At high iodineconcentrations in the presence of iodide there is a strong tendency forthe tri-iodide ion to form. We believe that this ion has very littleantimicrobial activity but can still be absorbed with the risk ofsystemic toxicity.

We have found that it is possible to prepare a composition which iscapable of generating iodine at a rate and level that makes it suitablefor use in wounds. This is achieved by separating certain of theingredients and controlling the kinetics of the generation of iodinethrough the manipulation of pH.

Accordingly the present invention provides an iodine preparationcomposition suitable for use on wounds comprising an iodide source, anoxidant and a buffer characterised in that the oxidant is heldseparately from the iodide until the point of use, and that the bufferis capable of maintaining the pH of the composition at between pH 4.5and pH 6 so that iodine is generated at a physiologically acceptable andefficacious rate.

The invention allows the preparation of compositions generating a lowbut effective iodine level for example up to about 2000 μg per g ofcomposition per hour, preferably in the range of 5 μg per g ofcomposition per hour to 1500 μg per g of composition per hour, morepreferably in the range 50 μg per g of composition per hour to 1000 μgper g of composition per hour so that the amount of free iodineavailable for antisepsis at any time is at least 0.001%.

The compositions of the invention are preferably formulated to generatethe above levels of iodine over a period of about 3 days.

The pH of the composition of the invention is generally below 5.8. Wehave found that if the pH is greater than about 6, the rate ofproduction of iodine by reaction of the oxidising agent with iodide ionsis too low to balance any losses of iodine by reaction with the organicmatter. We have found that it is generally desired that the pH of thecompositions is not below about 4.5 as otherwise there is a danger thatthe rate of oxidation of the iodide ions will be too fast with theresult that the composition could become toxic.

The desired pH of the compositions may be achieved by incorporatingbuffering agents therein. Examples of buffering agents which may beincluded are citric acid/disodium hydrogen phosphate, citric acid/sodiumcitrate, acetic acid/sodium acetate. The buffering agent mayconveniently be present in an amount of about 2% to 10%, preferablyabout 4% to 6% by weight and particularly about 5% by weight so as toprovide an isotonic composition.

The amount of oxidant in the composition is tailored to provide astoichiometric match with iodide. Preferably the oxidant is iodate andis provided in a molar ratio of 1:5 with iodide. In this way the iodidepresent in the composition fully reacts with all the oxidant. To providethe levels and rate of production of iodine in the range described aboveit is desirable to include up to 2% by weight of iodide, preferably,from 0.2% to 2% by weight of iodide. Iodide and iodate are preferablypresent as sodium salts although other usual counter ions may be used.

Convenient forms of administration of the composition include aqueousgels, films, creams, tablets and capsules.

The following examples are illustrative of the present invention.

EXAMPLE 1

Gel A Weight g Hydroxyethyl cellulose 30.00 Propylene Glycol 150.00Na₂HPO₄ 35.61 Citric Acid 21.01 Potassium Iodate 1.124 Water 762.256 GelB Weight in g Hydroxyethyl cellulose 30.0 Propylene Glycol 150.0Potassium Iodide 4.36 Water 815.64

Gel A was made by dissolving the buffer salt in a water/propylene glycolmix and then adding the iodate. When the solution is clear thehydroxyethyl cellulose is added and mixed until gelation is complete.Gel B was made by dissolving iodide in a water/propylene glycol mix.Hydroxyethyl cellulose was added to this mixture and mixed untilgelation was complete.

The gels were packaged in separate syringes which were bound togetherwith their nozzles fitted into a Y-shaped connecter. The contents weresterilised by autoclaving at 121 C for 15 minutes. Simultaneousdepression of the plungers allows the gels to be co-extruded and allowsthe gels to react while being dispensed into a wound. The co-extrusionof the gels results in a product producing approximately 100 μg per g ofcomposition per hour at a pH of about 5.4. The composition generated agreater than 5 log kill of S. aureous (NCIMB 9518) which is regarded asbeing an acceptable level of antimicrobial activity.

EXAMPLE 2

Film A g Hydroxypropylcellulose 16 Propylene Glycol 4 Potassium Iodate0.1124 Sodium phosphate 1.7805 Citric acid 1.0505 Water 77.0566 Film BHydroxypropylcellulose 16 Propylene Glycol 4 Potassium Iodide 0.436Water 79.564

The films are produced by knife over roller coating of aqueous solutiononto an inert carrier followed by drying at a temperature not exceeding100 C and sterilised by gamma irradiation.

The films may be cut into rectangles and added to a wound whereupon theydissolve in the wound fluid and reaction takes place.

1. An iodine preparation suitable for use on wounds comprising: (A) afirst part comprising an iodide source; and (B) a second part comprisingan oxidant and a buffer; wherein (1) said first part and said secondpart are combined at the point of use, (2) when said first part and saidsecond part are combined, the iodide source is present in an amount thatis 0.2 to 2 wt % of the combined two parts, (3) when said first part andsaid second part are combined at the point of use, the buffer maintainsthe pH of the combined two parts at between 4.5 and 6, and (4) when saidfirst part and said second part are combined at the point of use, iodineis generated at a rate of 5 to 1500 micrograms per one gram of thecombined two parts per hour.
 2. The iodine preparation as claimed inclaim 1 characterized in that the combined iodide source, oxidant andbuffer generates 100 μg of iodine per g of combination per hour.
 3. Theiodine preparation as claimed in claim 1 formulated so that the combinediodide source, oxidant and buffer generates the said levels of iodineover a period of three days.
 4. The iodine preparation as claimed inclaim 1 wherein the pH of the combined iodide source, oxidant and bufferis maintained between about 5.4 and 5.8.
 5. A method of treating a woundcomprising applying to said wound an effective wound treating amount ofan iodine preparation as claimed in claim
 1. 6. A method of treatingsepsis in wounds comprising applying to said wound an effective sepsistreating amount of an iodine preparation as claimed in claim 1.